This proposal for a Dentist Scientist Award will provide the candidate with a broad knowledge in the clinical aspects and basic sciences concerned with oral mucosa. The basic science portion of the training emphasizes biochemistry, molecular biology, and cell biology. The research portion deals with regulation of differentiation of oral epithelia by retinoids. Clinical training is in the Oral Medicine program, which emphasizes clinical diagnosis and treatment of oral mucosal disorders. These three aspects of training will provide the candidate with a well rounded outlook on health related issues of oral mucosa. The oral mucosa exhibit regional variation in accordance with function. The variation in terminal differentiation of the oral epithelia is reflected in the expression of structural proteins such as the keratins. The PH.D research project in this proposal is designed to investigate the effects of retinoids on the differentiation of oral epithelia and to determine the involvement of retinoid acid receptors (RARs) in differentiation. The working hypothesis is that region-specific expression of various RAR subtypes exerts regulatory control on the terminal differentiation programs in oral epithelia. In Aim 1 the possible correlation between the effects of retinoid acid (RA) on the differentiation of cultured oral epithelial cells and their expression of RAR genes will be investigated. The cells will be grown in various concentrations of RA in the Dermal Equivalent tissue culture system and their program of differentiation will be analyzed by immunohistochemistry and biochemical techniques for keratins and other structural proteins. RAR gene expression will be analyzed by in situ hybridization, Northern mRNA analysis, or RNase protection. Aim 2 is to directly prove the influence of specific RAR subtypes on epithelial cell differentiation. A specific RAR subtype will be overexpressed and underexpressed in the oral epithelial cells. This will be achieved by the use of retroviral vectors carrying the coding strand and the non-coding strand of the specific RAR cDNA, respectively. The effects on terminal differentiation of these transfected oral epithelial cells will be studied as described for the first part of the project. This project will enhance our understanding of the regulatory mechanisms of epithelial cell differentiation by retinoid acid at the molecular level.